In man, normal urinary bladder contractions are mediated, in part, through cholinergic muscarinic receptor stimulation. Muscarinic receptors not only mediate, in part, normal bladder contractions, but also may mediate the main part of the contractions in the overactive bladder resulting in symptoms such as urinary frequency, urgency and urge urinary incontinence.
After administration of Fesoterodine and other phenolic monoesters of formula (I) to mammals, such as humans, these compounds are cleaved by esterases to form the Active Metabolite within the body. The Active Metabolite is known to be a potent and competitive muscarinic receptor antagonist (WO 94/11337). Fesoterodine and other phenolic esters of the formula (I) thus represent potential prodrugs for the Active Metabolite. Fesoterodine, in particular, has been shown to be an effective drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency, as well as detrusor hyperactivity (as described in U.S. Pat. No. 6,713,464 and EP-B-1,077,912).
A synthetic approach for the production of the Active Metabolite and monoesters of the phenolic hydroxy group of the Active Metabolite such as Fesoterodine has been described in U.S. Pat. No. 6,713,464 as follows:
In a first step, an ethereal solution is prepared from R-(−)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine, ethyl bromide and magnesium; this solution is diluted with dry THF and is cooled to −60° C.
In a second step, powdered solid carbon dioxide is added in small portions and the reaction mixture is warmed to room temperature.
In a third step, the reaction is quenched with an aqueous solution of ammonium chloride.
In a fourth step, the aqueous phase of the quenched reaction mixture is adjusted to pH 0.95.
In a fifth step, the pH adjusted phase is filtered and R-(−)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride can be recovered from the solid.
In a sixth step, the resulting purified benzoic acid is esterified to its corresponding methyl ester. A diagram summarizing this multi-step synthesis is shown below.

U.S. Pat. No. 6,713,464 further describes converting the methyl ester to the Active Metabolite, and then esterifying the Active Metabolite to a phenolic monoester, such as Fesoterodine.
WO 94/11337 also describes a multi-stage process to synthesize the precursor to the Active Metabolite.
These previously described methods for producing the Active Metabolite require numerous steps that result in complex purification procedures, time-delay, and enhanced possibility of human error, thereby prohibiting optimal efficiency and cost-effectiveness. Also, the solid carbon dioxide used in the art is difficult to handle on large scale due to the need to work at very low temperatures and to add the crushed dry ice portion-wise, and due to the difficulties to control the very exothermic nature of the reaction.
The present disclosure aims to overcome these problems and disadvantages. It has been found that the use of a di(C1-C6 alkyl)carbonate, preferably dimethylcarbonate, or the use of a cyclic C1-C6 alkylene carbonate, in the Grignard reaction results in a highly pure product, while at the same time eliminating the production of the benzoic acid and the purification thereof.
The methods disclosed herein are unexpected and are surprising since current and well-known textbooks teach that the addition of Grignard reagents to carbonates and other esters produces tertiary alcohols as a predominant product. For example, in F. A. Carey, R. J. Sundberg, “Advanced Organic Chemistry”, Springer Media, 2001, it is taught that the addition of Grignard reagents to esters (including carbonates) is commonly used to produce tertiary alcohols (pages 447-448). Likewise, the well-known compendium “March's Advanced Organic Chemistry”, Wilex-Interscience Publication, John Wiley & Sons, Inc., 5th edition, 2001, page 1214, teaches that in Grignard reactions “carbonates give tertiary alcohol in which all three R groups are the same” (page 1214).
Surprisingly, however, in the presently described method the reaction of a carbonate with a Grignard reagent, which is formed after the addition of magnesium and a Grignard initiator to a compound of formula (II), leads to an alkyl ester of formula (III) as the predominate product, while the tertiary alcohol is only formed as a by-product. Typically, between about 60% and about 70% of the direct reaction products of the presently described Grignard reaction is a compound of formula (III).
Also, it turned out, surprisingly, that the tertiary alcohol and other impurities formed during the presently described methods can be easily and very effectively removed during the crystallisation of the ester of formula (III) in isopropanol. This was not predictable from the state of the art.
Accordingly, the use of carbonates, such as dimethylcarbonate or a higher homologue thereof, in the Grignard reaction allows for a shortened and more cost-effective synthetic approach to compounds of formula (I) by eliminating the production of the benzoic acid intermediate and the purification thereof. Moreover, the current methods are better suited for a process on large scale than the reaction requiring solid carbon dioxide that is known from the art.
Moreover, it has been unexpectedly found that the use of methyl magnesium chloride as the Grignard initiator is particularly advantageous. The purity of formula (III) after isopropanol crystallization is typically between about 96.1 and 97.4% when methyl magnesium chloride is used to start the Grignard reaction, whereas the purity of the compound of formula (III) did not exceed about 94% in three batches produced with isopropyl magnesium bromide as the Grignard initiator.